SH2B3 inactivation through CN-LOH 12q is uniquely associated with B-cell precursor ALL with iAMP21 or other chromosome 21 gain
In more than 30% of B-cell precursor acute lymphoblastic leukaemia (B-ALL), chromosome 21 sequence is overrepresented through aneuploidy or structural rearrangements, exemplified by intrachromosomal amplification of chromosome 21 (iAMP21). Although frequent, the mechanisms by which these abnormaliti...
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| Veröffentlicht in: | Leukemia 2019-08, Vol.33 (8), p.1881-1894 |
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| creator | Sinclair, Paul B. Ryan, Sarra Bashton, Matthew Hollern, Shaun Hanna, Rebecca Case, Marian Schwalbe, Edward C. Schwab, Claire J. Cranston, Ruth E. Young, Brian D. Irving, Julie A. E. Vora, Ajay J. Moorman, Anthony V. Harrison, Christine J. |
| description | In more than 30% of B-cell precursor acute lymphoblastic leukaemia (B-ALL), chromosome 21 sequence is overrepresented through aneuploidy or structural rearrangements, exemplified by intrachromosomal amplification of chromosome 21 (iAMP21). Although frequent, the mechanisms by which these abnormalities promote B-ALL remain obscure. Intriguingly, we found copy number neutral loss of heterozygosity (CN-LOH) of 12q was recurrent in iAMP21-ALL, but never observed in B-ALL without some form of chromosome 21 gain. As a consequence of CN-LOH 12q, mutations or deletions of the adaptor protein,
SH2B3
, were converted to homozygosity. In patients without CN-LOH 12q, bi-allelic abnormalities of
SH2B3
occurred, but only in iAMP21-ALL, giving an overall incidence of 18% in this sub-type. Review of published data confirmed a tight association between overrepresentation of chromosome 21 and both CN-LOH 12q and
SH2B3
abnormalities in B-ALL. Despite relatively small patient numbers, preliminary analysis linked 12q abnormalities to poor outcome in iAMP21-ALL (
p
= 0.03). Homology modelling of a leukaemia-associated SH2 domain mutation and in vitro analysis of patient-derived xenograft cells implicated the JAK/STAT pathway as one likely target for SH2B3 tumour suppressor activity in iAMP21-ALL. |
| doi_str_mv | 10.1038/s41375-019-0412-1 |
| format | Article |
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SH2B3
, were converted to homozygosity. In patients without CN-LOH 12q, bi-allelic abnormalities of
SH2B3
occurred, but only in iAMP21-ALL, giving an overall incidence of 18% in this sub-type. Review of published data confirmed a tight association between overrepresentation of chromosome 21 and both CN-LOH 12q and
SH2B3
abnormalities in B-ALL. Despite relatively small patient numbers, preliminary analysis linked 12q abnormalities to poor outcome in iAMP21-ALL (
p
= 0.03). Homology modelling of a leukaemia-associated SH2 domain mutation and in vitro analysis of patient-derived xenograft cells implicated the JAK/STAT pathway as one likely target for SH2B3 tumour suppressor activity in iAMP21-ALL.</description><identifier>ISSN: 0887-6924</identifier><identifier>EISSN: 1476-5551</identifier><identifier>DOI: 10.1038/s41375-019-0412-1</identifier><identifier>PMID: 30816328</identifier><language>eng</language><publisher>London: Nature Publishing Group UK</publisher><subject>38/22 ; 38/32 ; 45/23 ; 45/61 ; 631/67/1990/283/2125 ; 631/67/395 ; 631/67/69 ; 692/308/2056 ; 96/1 ; 96/21 ; Abnormalities ; Acute lymphoblastic leukemia ; Adaptor Proteins, Signal Transducing ; Aneuploidy ; Cancer Research ; Chromosome 21 ; Chromosome Aberrations ; Chromosomes ; Chromosomes, Human, Pair 12 ; Chromosomes, Human, Pair 21 ; Copy number ; Critical Care Medicine ; Deactivation ; Hematology ; Heterozygosity ; Homology ; Homozygosity ; Humans ; Inactivation ; Intensive ; Interleukin-7 - pharmacology ; Internal Medicine ; Intracellular Signaling Peptides and Proteins ; Leukemia ; Loss of Heterozygosity ; Lymphocytes B ; Medicine ; Medicine & Public Health ; Mutation ; Oncology ; Precursor B-Cell Lymphoblastic Leukemia-Lymphoma - genetics ; Precursors ; Proteins - genetics ; STAT5 Transcription Factor - physiology ; Tumors ; Xenografts ; Xenotransplantation</subject><ispartof>Leukemia, 2019-08, Vol.33 (8), p.1881-1894</ispartof><rights>The Author(s) 2019</rights><rights>This work is published under http://creativecommons.org/licenses/by/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c470t-4ba88b11be2d44efc930cac279e8bcb0a218648c1035859d5ddc038f4562106d3</citedby><cites>FETCH-LOGICAL-c470t-4ba88b11be2d44efc930cac279e8bcb0a218648c1035859d5ddc038f4562106d3</cites><orcidid>0000-0002-1190-9469</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://link.springer.com/content/pdf/10.1038/s41375-019-0412-1$$EPDF$$P50$$Gspringer$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://link.springer.com/10.1038/s41375-019-0412-1$$EHTML$$P50$$Gspringer$$Hfree_for_read</linktohtml><link.rule.ids>230,314,776,780,881,27903,27904,41467,42536,51298</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/30816328$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Sinclair, Paul B.</creatorcontrib><creatorcontrib>Ryan, Sarra</creatorcontrib><creatorcontrib>Bashton, Matthew</creatorcontrib><creatorcontrib>Hollern, Shaun</creatorcontrib><creatorcontrib>Hanna, Rebecca</creatorcontrib><creatorcontrib>Case, Marian</creatorcontrib><creatorcontrib>Schwalbe, Edward C.</creatorcontrib><creatorcontrib>Schwab, Claire J.</creatorcontrib><creatorcontrib>Cranston, Ruth E.</creatorcontrib><creatorcontrib>Young, Brian D.</creatorcontrib><creatorcontrib>Irving, Julie A. E.</creatorcontrib><creatorcontrib>Vora, Ajay J.</creatorcontrib><creatorcontrib>Moorman, Anthony V.</creatorcontrib><creatorcontrib>Harrison, Christine J.</creatorcontrib><title>SH2B3 inactivation through CN-LOH 12q is uniquely associated with B-cell precursor ALL with iAMP21 or other chromosome 21 gain</title><title>Leukemia</title><addtitle>Leukemia</addtitle><addtitle>Leukemia</addtitle><description>In more than 30% of B-cell precursor acute lymphoblastic leukaemia (B-ALL), chromosome 21 sequence is overrepresented through aneuploidy or structural rearrangements, exemplified by intrachromosomal amplification of chromosome 21 (iAMP21). Although frequent, the mechanisms by which these abnormalities promote B-ALL remain obscure. Intriguingly, we found copy number neutral loss of heterozygosity (CN-LOH) of 12q was recurrent in iAMP21-ALL, but never observed in B-ALL without some form of chromosome 21 gain. As a consequence of CN-LOH 12q, mutations or deletions of the adaptor protein,
SH2B3
, were converted to homozygosity. In patients without CN-LOH 12q, bi-allelic abnormalities of
SH2B3
occurred, but only in iAMP21-ALL, giving an overall incidence of 18% in this sub-type. Review of published data confirmed a tight association between overrepresentation of chromosome 21 and both CN-LOH 12q and
SH2B3
abnormalities in B-ALL. Despite relatively small patient numbers, preliminary analysis linked 12q abnormalities to poor outcome in iAMP21-ALL (
p
= 0.03). Homology modelling of a leukaemia-associated SH2 domain mutation and in vitro analysis of patient-derived xenograft cells implicated the JAK/STAT pathway as one likely target for SH2B3 tumour suppressor activity in iAMP21-ALL.</description><subject>38/22</subject><subject>38/32</subject><subject>45/23</subject><subject>45/61</subject><subject>631/67/1990/283/2125</subject><subject>631/67/395</subject><subject>631/67/69</subject><subject>692/308/2056</subject><subject>96/1</subject><subject>96/21</subject><subject>Abnormalities</subject><subject>Acute lymphoblastic leukemia</subject><subject>Adaptor Proteins, Signal Transducing</subject><subject>Aneuploidy</subject><subject>Cancer Research</subject><subject>Chromosome 21</subject><subject>Chromosome Aberrations</subject><subject>Chromosomes</subject><subject>Chromosomes, Human, Pair 12</subject><subject>Chromosomes, Human, Pair 21</subject><subject>Copy number</subject><subject>Critical Care Medicine</subject><subject>Deactivation</subject><subject>Hematology</subject><subject>Heterozygosity</subject><subject>Homology</subject><subject>Homozygosity</subject><subject>Humans</subject><subject>Inactivation</subject><subject>Intensive</subject><subject>Interleukin-7 - pharmacology</subject><subject>Internal Medicine</subject><subject>Intracellular Signaling Peptides and Proteins</subject><subject>Leukemia</subject><subject>Loss of Heterozygosity</subject><subject>Lymphocytes B</subject><subject>Medicine</subject><subject>Medicine & Public Health</subject><subject>Mutation</subject><subject>Oncology</subject><subject>Precursor B-Cell Lymphoblastic Leukemia-Lymphoma - genetics</subject><subject>Precursors</subject><subject>Proteins - genetics</subject><subject>STAT5 Transcription Factor - physiology</subject><subject>Tumors</subject><subject>Xenografts</subject><subject>Xenotransplantation</subject><issn>0887-6924</issn><issn>1476-5551</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2019</creationdate><recordtype>article</recordtype><sourceid>C6C</sourceid><sourceid>EIF</sourceid><sourceid>ABUWG</sourceid><sourceid>AFKRA</sourceid><sourceid>AZQEC</sourceid><sourceid>BENPR</sourceid><sourceid>CCPQU</sourceid><sourceid>DWQXO</sourceid><sourceid>GNUQQ</sourceid><recordid>eNp1kU2PFCEQhonRuOPqD_BiSLx4QSkaaPpiMjtRx2T8SNQzoWlmmk13Mwv0mr3422XS6_qReCKp96mXqnoRegr0JdBKvUocqloQCg2hHBiBe2gFvJZECAH30YoqVRPZMH6GHqV0SelJlA_RWUUVyIqpFfrxZcsuKuwnY7O_NtmHCec-hvnQ481Hsvu0xcCusE94nvzV7IYbbFIK1pvsOvzd5x5fEOuGAR-js3NMIeL1brcofv3hMwNcSiH3LmJbjMeQwuhwKR-Mnx6jB3szJPfk9j1H396--brZlo_fvd-sd8TymmbCW6NUC9A61nHu9rapqDWW1Y1TrW2pYaAkV7ZcRSjRdKLrbDnQngvJgMquOkevF9_j3I6us27K0Qz6GP1o4o0Oxuu_lcn3-hCutayFpIwXgxe3BjGUM6SsR59Oe5vJhTnpMkBduJJCQZ__g16GOU5lPc2YbDhQXtFCwULZGFKKbn83DFB9Slcv6eqSrj6lq6H0PPtzi7uOX3EWgC1AKtJ0cPH31_93_Qlioq6j</recordid><startdate>20190801</startdate><enddate>20190801</enddate><creator>Sinclair, Paul B.</creator><creator>Ryan, Sarra</creator><creator>Bashton, Matthew</creator><creator>Hollern, Shaun</creator><creator>Hanna, Rebecca</creator><creator>Case, Marian</creator><creator>Schwalbe, Edward C.</creator><creator>Schwab, Claire J.</creator><creator>Cranston, Ruth E.</creator><creator>Young, Brian D.</creator><creator>Irving, Julie A. 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E. ; Vora, Ajay J. ; Moorman, Anthony V. ; Harrison, Christine J.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c470t-4ba88b11be2d44efc930cac279e8bcb0a218648c1035859d5ddc038f4562106d3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2019</creationdate><topic>38/22</topic><topic>38/32</topic><topic>45/23</topic><topic>45/61</topic><topic>631/67/1990/283/2125</topic><topic>631/67/395</topic><topic>631/67/69</topic><topic>692/308/2056</topic><topic>96/1</topic><topic>96/21</topic><topic>Abnormalities</topic><topic>Acute lymphoblastic leukemia</topic><topic>Adaptor Proteins, Signal Transducing</topic><topic>Aneuploidy</topic><topic>Cancer Research</topic><topic>Chromosome 21</topic><topic>Chromosome Aberrations</topic><topic>Chromosomes</topic><topic>Chromosomes, Human, Pair 12</topic><topic>Chromosomes, Human, Pair 21</topic><topic>Copy number</topic><topic>Critical Care Medicine</topic><topic>Deactivation</topic><topic>Hematology</topic><topic>Heterozygosity</topic><topic>Homology</topic><topic>Homozygosity</topic><topic>Humans</topic><topic>Inactivation</topic><topic>Intensive</topic><topic>Interleukin-7 - pharmacology</topic><topic>Internal Medicine</topic><topic>Intracellular Signaling Peptides and Proteins</topic><topic>Leukemia</topic><topic>Loss of Heterozygosity</topic><topic>Lymphocytes B</topic><topic>Medicine</topic><topic>Medicine & Public Health</topic><topic>Mutation</topic><topic>Oncology</topic><topic>Precursor B-Cell Lymphoblastic Leukemia-Lymphoma - genetics</topic><topic>Precursors</topic><topic>Proteins - genetics</topic><topic>STAT5 Transcription Factor - physiology</topic><topic>Tumors</topic><topic>Xenografts</topic><topic>Xenotransplantation</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Sinclair, Paul B.</creatorcontrib><creatorcontrib>Ryan, Sarra</creatorcontrib><creatorcontrib>Bashton, Matthew</creatorcontrib><creatorcontrib>Hollern, Shaun</creatorcontrib><creatorcontrib>Hanna, Rebecca</creatorcontrib><creatorcontrib>Case, Marian</creatorcontrib><creatorcontrib>Schwalbe, Edward C.</creatorcontrib><creatorcontrib>Schwab, Claire J.</creatorcontrib><creatorcontrib>Cranston, Ruth E.</creatorcontrib><creatorcontrib>Young, Brian D.</creatorcontrib><creatorcontrib>Irving, Julie A. E.</creatorcontrib><creatorcontrib>Vora, Ajay J.</creatorcontrib><creatorcontrib>Moorman, Anthony V.</creatorcontrib><creatorcontrib>Harrison, Christine J.</creatorcontrib><collection>Springer Nature OA Free Journals</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>ProQuest Central (Corporate)</collection><collection>Bacteriology Abstracts (Microbiology B)</collection><collection>Nursing & Allied Health Database</collection><collection>Immunology Abstracts</collection><collection>Industrial and Applied Microbiology Abstracts (Microbiology A)</collection><collection>Nucleic Acids Abstracts</collection><collection>Oncogenes and Growth Factors Abstracts</collection><collection>Virology and AIDS Abstracts</collection><collection>Health & Medical Collection</collection><collection>ProQuest Central (purchase pre-March 2016)</collection><collection>Medical Database (Alumni Edition)</collection><collection>ProQuest Pharma Collection</collection><collection>Public Health Database</collection><collection>Technology Research Database</collection><collection>ProQuest SciTech Collection</collection><collection>ProQuest Natural Science Collection</collection><collection>Hospital Premium Collection</collection><collection>Hospital Premium Collection (Alumni Edition)</collection><collection>ProQuest Central (Alumni) (purchase pre-March 2016)</collection><collection>ProQuest Central (Alumni Edition)</collection><collection>ProQuest Central UK/Ireland</collection><collection>ProQuest Central Essentials</collection><collection>Biological Science Collection</collection><collection>ProQuest Central</collection><collection>Natural Science Collection</collection><collection>Environmental Sciences and Pollution Management</collection><collection>ProQuest One Community College</collection><collection>ProQuest Central Korea</collection><collection>Engineering Research Database</collection><collection>Health Research Premium Collection</collection><collection>Health Research Premium Collection (Alumni)</collection><collection>ProQuest Central Student</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>SciTech Premium Collection</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>Nursing & Allied Health Database (Alumni Edition)</collection><collection>ProQuest Biological Science Collection</collection><collection>Health & Medical Collection (Alumni Edition)</collection><collection>Medical Database</collection><collection>Algology Mycology and Protozoology Abstracts (Microbiology C)</collection><collection>Biological Science Database</collection><collection>Nursing & Allied Health Premium</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>ProQuest One Academic Eastern Edition (DO NOT USE)</collection><collection>ProQuest One Academic</collection><collection>ProQuest One Academic UKI Edition</collection><collection>ProQuest Central China</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Leukemia</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Sinclair, Paul B.</au><au>Ryan, Sarra</au><au>Bashton, Matthew</au><au>Hollern, Shaun</au><au>Hanna, Rebecca</au><au>Case, Marian</au><au>Schwalbe, Edward C.</au><au>Schwab, Claire J.</au><au>Cranston, Ruth E.</au><au>Young, Brian D.</au><au>Irving, Julie A. E.</au><au>Vora, Ajay J.</au><au>Moorman, Anthony V.</au><au>Harrison, Christine J.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>SH2B3 inactivation through CN-LOH 12q is uniquely associated with B-cell precursor ALL with iAMP21 or other chromosome 21 gain</atitle><jtitle>Leukemia</jtitle><stitle>Leukemia</stitle><addtitle>Leukemia</addtitle><date>2019-08-01</date><risdate>2019</risdate><volume>33</volume><issue>8</issue><spage>1881</spage><epage>1894</epage><pages>1881-1894</pages><issn>0887-6924</issn><eissn>1476-5551</eissn><abstract>In more than 30% of B-cell precursor acute lymphoblastic leukaemia (B-ALL), chromosome 21 sequence is overrepresented through aneuploidy or structural rearrangements, exemplified by intrachromosomal amplification of chromosome 21 (iAMP21). Although frequent, the mechanisms by which these abnormalities promote B-ALL remain obscure. Intriguingly, we found copy number neutral loss of heterozygosity (CN-LOH) of 12q was recurrent in iAMP21-ALL, but never observed in B-ALL without some form of chromosome 21 gain. As a consequence of CN-LOH 12q, mutations or deletions of the adaptor protein,
SH2B3
, were converted to homozygosity. In patients without CN-LOH 12q, bi-allelic abnormalities of
SH2B3
occurred, but only in iAMP21-ALL, giving an overall incidence of 18% in this sub-type. Review of published data confirmed a tight association between overrepresentation of chromosome 21 and both CN-LOH 12q and
SH2B3
abnormalities in B-ALL. Despite relatively small patient numbers, preliminary analysis linked 12q abnormalities to poor outcome in iAMP21-ALL (
p
= 0.03). Homology modelling of a leukaemia-associated SH2 domain mutation and in vitro analysis of patient-derived xenograft cells implicated the JAK/STAT pathway as one likely target for SH2B3 tumour suppressor activity in iAMP21-ALL.</abstract><cop>London</cop><pub>Nature Publishing Group UK</pub><pmid>30816328</pmid><doi>10.1038/s41375-019-0412-1</doi><tpages>14</tpages><orcidid>https://orcid.org/0000-0002-1190-9469</orcidid><oa>free_for_read</oa></addata></record> |
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| subjects | 38/22 38/32 45/23 45/61 631/67/1990/283/2125 631/67/395 631/67/69 692/308/2056 96/1 96/21 Abnormalities Acute lymphoblastic leukemia Adaptor Proteins, Signal Transducing Aneuploidy Cancer Research Chromosome 21 Chromosome Aberrations Chromosomes Chromosomes, Human, Pair 12 Chromosomes, Human, Pair 21 Copy number Critical Care Medicine Deactivation Hematology Heterozygosity Homology Homozygosity Humans Inactivation Intensive Interleukin-7 - pharmacology Internal Medicine Intracellular Signaling Peptides and Proteins Leukemia Loss of Heterozygosity Lymphocytes B Medicine Medicine & Public Health Mutation Oncology Precursor B-Cell Lymphoblastic Leukemia-Lymphoma - genetics Precursors Proteins - genetics STAT5 Transcription Factor - physiology Tumors Xenografts Xenotransplantation |
| title | SH2B3 inactivation through CN-LOH 12q is uniquely associated with B-cell precursor ALL with iAMP21 or other chromosome 21 gain |
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